Codeine is commonly used in combination analgesic products. The use of codeine during breastfeeding can rarely be associated with serious adverse effects related to genetic polymorphisms affecting codeine's metabolism and disposition. Clinicians treating infants of breastfeeding mothers should be aware of this rare but potentially serious complication.

Labetalol is widely prescribed as a first-line antihypertensive in pregnancy; however, rare but potentially severe idiosyncratic hepatotoxicity has been reported, with a disproportionately strong reporting signal for liver injury relative to other β-blockers. In this report, a fatal case is described in which mild initial symptoms rapidly progressed to fulminant hepatocellular injury and acute liver failure within days, underscoring the importance of early recognition of drug-induced liver injury and prompt discontinuation of labetalol. A PRISMA-guided systematic review of MEDLINE, Embase, CINAHL, Cochrane Library, PubMed, and Google Scholar (from inception to December 2025) identified 27 published case reports. Patients were predominantly female (≈80%), and one-third were pregnant or postpartum. Latency ranged from 7 to 365 days (median ≈60 days). The injury phenotype was consistently hepatocellular, often with autoimmune-like serologic or histologic features. Outcomes included full recovery in most (≈75%), but also liver transplantation and death. In the FDA Adverse Event Reporting System (2020Q1-2025Q1), labetalol showed strong disproportionality signals for DILI (PRR 22.7, 95% CI 15.6-33.1; ROR 23.7, 95% CI 16.0-35.1; IC025 2.5) and autoimmune hepatitis (PRR 59.8, 95% CI 34.1-104.8; ROR 60.9, 95% CI 34.4-108.1; IC025 2.8), which persisted when restricted to other β-blockers as comparators. Signals for acute hepatic failure and hyperbilirubinemia were elevated but less statistically robust. The available evidence is consistent with a clinically meaningful and biologically plausible association between labetalol and idiosyncratic hepatotoxicity, supporting heightened clinical awareness and further mechanistic and population-based study.

AIMS:Adverse drug reactions (ADRs) are a common problem in paediatric health care. There is limited access to expertise in the evaluation and management of potential ADRs in children, limiting access to these services and creating delays in assessment and management. The purpose of this study was to evaluate the real world experience of, and satisfaction with, a virtual paediatric ADR clinic based in London, Canada during the COVID-19 pandemic. METHODS:This was done using a mixed methods approach with a retrospective chart review from an online database and satisfaction surveys with patient families and referring clinicians. RESULTS:We found that 225 ADRs were assessed virtually over 3 years, with an average referral time of 23 days and 43.6% of patients residing in distant rural and urban communities. Further testing (most commonly DPT, RAST, and LTA) was recommended for 89.3% of patients. Whereas a number of results were pending, 17.2% and 43.5% of tests ordered were positive and negative, respectively, demonstrating success in allergy de-labelling. A high level of satisfaction was reported by patient families (95.0%) and referring physicians (93.3%) that responded to the survey. CONCLUSIONS:This study demonstrated the ability of a virtual clinic in a real-world setting to efficiently assess and triage children with suspected ADRs and suggests that telemedicine may be a feasible way to improve access to specialized ADR services for children.

While proton pump inhibitors (PPIs) are widely recognized for their effectiveness in treating gastroesophageal reflux disease in older children and adults, their use in infants is controversial due to the paucity of well-controlled studies demonstrating clear benefits. Furthermore, concerns about potential adverse effects, such as increased risks of gastrointestinal and respiratory infections, nutrient malabsorption and alterations in gut microbiota, complicate the decision-making process for health care providers and care givers. The current guidelines emphasize nonpharmacologic management for infantile reflux and recommend PPIs for very specific indications. Despite this, PPIs continue to be widely prescribed to infants.

INTRODUCTION:Idiosyncratic adverse drug reactions (IADRs) or drug hypersensitivity reactions (DHRs) represent a major health problem because they are unpredictable and can be severe with potential life-long or even lethal consequences. Their pathophysiology is not clear but thought to be immune mediated, supported by the significant statistical association of these reactions with specific alleles of the human leukocyte antigen (HLA) gene. AREA COVERED:This comprehensive update review summarizes the currently available evidence on the role of HLA gene locus in IADRs and discusses the present understanding of the pathophysiology of IADRs. We searched the available literature in PubMed and Google Scholar with no date restriction for publications on HLA and adverse drug reactions. Findings are summarized and discussed in the context of the currently available evidence. EXPERT OPINION:The role of the immune system in IADRs and the role of pharmacogenetic testing in this field is evident. HLA genetic testing is very promising in the management of these reactions. Many obstacles seem to prevent pharmacogenetic testing to meet its full potential including cost and health care providers' education. Further work in needed to provide more evidence and allow widespread use of pharmacogenetic testing in the clinical practice.

Oral ibuprofen is the preferred pharmacotherapeutic option for treatment of a persistent patent ductus arteriosus (PDA), but evidence for its optimal use in extremely low gestational age newborns (ELGANs) remains limited. In the current study, we aimed to investigate the pharmacokinetics and exposure‐response relationship of oral ibuprofen in ELGANs of ≤72 h postnatal age (PNA) on standard (SD) versus those >72 h PNA on high‐dose (HD) regimen for closure of persistent PDA. This was a retrospective analysis of data from a previous population PK study of ELGANs with a persistent PDA treated with a SD (10–5–5 mg/kg/day, PNA <72 h) versus a HD (20–10–10 mg/kg/day, PNA >72 h) oral ibuprofen, with the primary aim of comparing degree of exposure, defined as AUC 0‐24 (AUC from time 0 to 24 h). Twelve ELGANs received SD versus 11 receiving HD oral ibuprofen. The mean (SD) of exposure at 24 h (AUC 0‐24 h ) was 486 (128) and 509 (208) ( P = .41) and at 72 h (AUC 0‐72 h ) was 1529 (493) and 1510 (820) ( P = .94). Two (16%) ELGANs in the HD group developed severe gastrointestinal (GI) AEs and 1 (9%) in the SD had severe intraventricular hemorrhage. The use of SD and HD oral ibuprofen in ELGANs with PNA of <72 h and those >72 h, respectively, resulted in comparable exposure. The PNA‐dependent response to oral ibuprofen and exposure‐response relationship in ELGANs of higher PNA needs further investigation.

Violence, poor mental health, and harmful substance use are commonly experienced by female sex workers (FSWs) in sub-Saharan Africa, all of which are associated with increased HIV susceptibility. We aimed to investigate the associations between violence, poor mental health and harmful alcohol/substance use with hair cortisol concentration (HCC) levels as a potential biological pathway linking the experiences of these stressors and HIV vulnerability. We used the baseline data of the Maisha Fiti study of FSWs in Nairobi, Kenya. Participants reported recent violence, poor mental health, and harmful alcohol/substance use. Hair samples proximal to the scalp were collected to measure cortisol levels determined by ELISA. We analysed the data of 425 HIV-negative respondents who provided at least 2 cm of hair sample. The prevalence of recent violence was 89.3% (physical 54.6%; sexual 49.4%; emotional 77.0% and financial 66.5%), and 29.1% had been arrested due to sex work. 23.7% of participants reported moderate/severe depression, 11.6% moderate/severe anxiety, 13.5% PTSD and 10.8% recent suicidal thoughts and/or attempts. About half of the participants (48.8%) reported recent harmful alcohol and/or other substance use. In multivariable linear regression analyses, both physical and/or sexual violence (adjusted geometric mean ratio (aGMR) = 1.28; 95% CI 1.01-1.62) and harmful alcohol and/or other substance use (aGMR = 1.31; 95% CI 1.03-1.65) were positively and independently associated with increased HCC levels. Findings suggest a role of violence and substance use in elevated HCC levels, which could increase HIV risk due to cortisol-related T cell activation. However, longitudinal and mechanistic studies are needed to confirm this hypothesis.

Objectives Opioid-related deaths are an ongoing concern. There have been increasing numbers of fentanyl-related adult deaths with limited knowledge of the characteristics and circumstances of opioid toxicity deaths in children. Our aim was to address this using province-wide data capturing all deaths in children under the age of 10 years in Ontario.Methods Data were extracted from the opioid investigative aid database at the Office of the Chief Coroner from the implementation of the system from October 1, 2017, to October 31, 2021. This collects all opioid-related deaths in Ontario (population 14.7 million). A chart review was undertaken on all deaths under 10 years of age. Patient characteristics were calculated as percentages; descriptive analysis was conducted.Results Ten deaths in children under the age of 10 occurred during the study period. The average age was 1.9 years with the oldest being 4 years and 9 months. The causative opioid was fentanyl alone in four cases (40%), fentanyl and other drugs in four cases (40%), and hydromorphone and methadone in one case each (10%). Most cases involved improperly stored medication or illicit substances. All children who died had previous child protection service involvement, and at least 70% of their families had previous police involvement.Conclusions Fentanyl was the primary substance involved in 80% of deaths. Several potential areas of system change include education on fentanyl risk to young children, careful storage of illicit substances, and implications for how the child protection system intervenes in homes where the use of opioids and illicit substance use is reported to occur.

Etiology-associated definitions for blistering severe cutaneous adverse reactions in children were recently proposed to replace the existing terms Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and others (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/7mj555m5vr/1; Table I).1Ramien M.L. Bahubeshi A. Lara-Corrales I. et al.Blistering severe cutaneous adverse reactions in children: proposal for paediatric-focused clinical criteria.Br J Dermatol. 2021; 185: 447-449https://doi.org/10.1111/bjd.20063Crossref PubMed Scopus (13) Google Scholar In this multicenter retrospective cohort study, patients previously diagnosed with conditions on the Stevens-Johnson syndrome–toxic epidermal necrolysis spectrum were reclassified using the new definitions.2Canavan T.N. Mathes E.F. Frieden I. Shinkai K. Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review.J Am Acad Dermatol. 2015; 72: 239-245https://doi.org/10.1016/j.jaad.2014.06.026Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar,3Bastuji-Garin S. Rzany B. Stern R.S. Shear N.H. Naldi L. Roujeau J.C. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.Arch Dermatol. 1993; 129: 92-96https://doi.org/10.1001/archderm.1993.01680220104023Crossref PubMed Scopus (1393) Google Scholar In this report, we summarize the cohort features and reclassification results.Table ICase reclassification with the proposed pediatric-specific criteria for reactive infectious mucocutaneous eruption and drug-induced epidermal necrolysisCase identification diagnosisTotal cases, n (%)Reclassified as DEN, n (% of total cases)Reclassified as RIME, n (% of total cases)SJS136 (43.0)53 (49.0)83 (39.9)MIRM65 (20.6)0 (0)65 (31.2)TEN43 (13.6)40 (37.0)3 (1.4)EMM24 (7.6)0 (0)24 (11.5)MPAM18 (5.7)0 (0)18 (8.6)SJS-TEN overlap15 (4.7)12 (11.1)3 (1.4)Mucosal respiratory syndrome2 (0.6)0 (0)2 (0.96)Incomplete SJS7 (2.2)1 (0.9)6 (2.9)Fuchs' syndrome1 (0.3)0 (0)1 (0.5)Ectodermosis pluriorificialis1 (0.3)0 (0)1 (0.5)Three hundred sixteen patients were included from 1192 identified; most cases were excluded at collaborating sites due to incomplete information that prevented confirmation of the diagnosis.EMM, erythema multiforme major; MIRM, Mycoplasma pneumoniae–induced rash and mucositis; MPAM, Mycoplasma pneumoniae–associated rash and mucositis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. Open table in a new tab Three hundred sixteen patients were included from 1192 identified; most cases were excluded at collaborating sites due to incomplete information that prevented confirmation of the diagnosis. EMM, erythema multiforme major; MIRM, Mycoplasma pneumoniae–induced rash and mucositis; MPAM, Mycoplasma pneumoniae–associated rash and mucositis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. Institutional review board approval was obtained at 13 participating North American sites. The Research Electronic Data Capture (REDCap) database (http://project-redcap.org) was used for data collection from September 2019 to December 2020. Inclusion criteria were age <18 years at diagnosis, met reactive infectious mucocutaneous eruption (RIME) or drug-induced epidermal necrolysis (DEN) criteria, and hospitalized between January 2019 and 2000. Cases were identified by International Classification of Diseases (ICD) 9/10 coding or clinical diagnosis (Table I). Cases with unclear body surface area involved or length of hospitalization <1 day or where another diagnosis was possible were excluded. Cases were reclassified as RIME or DEN by site principal investigators (J.C., S.H., I.L.C., H.B.B., A.Y.K., L.C.S., L.A., C.L.W., M.R., J.S., S.A.G., S.S., and M.L.R.) and confirmed by 2 central independent reviewers (M.L.R. and I.L.C.). Three hundred sixteen of 1192 identified cases were eligible: 208 (66%) RIME and 108 (34%) DEN (Table II). Case identification diagnoses are compared to reclassified diagnoses in Table I, showing that Stevens-Johnson syndrome was the most heterogeneous diagnosis, made up of 60% RIME (83/136) and 40% DEN (53/136). Both RIME and DEN showed a male predominance that was more marked for RIME (70% male). Between-group differences were significant (Fisher exact test) for age, microbiological tests performed, and treatments given other than immunosuppressive therapies.Table IIPatient characteristicsDemographicsOverall, n (%)DEN, n (%)RIME, n (%)Patients316108 (34.2)208 (65.8)Age (y) <642 (13.3)25 (23.2)17 (8.2) 6-12182 (57.6)55 (50.9)127 (61.1) >12 to <1892 (29.1)25 (23.2)64 (30.8)Sex Male210 (66.5)64 (59.3)146 (70.2) Female106 (33.5)44 (40.7)62 (29.8)Microbiological tests HSV workup∗HSV workup included serology, polymerase chain reaction, and culture: "not performed" only if none of the 3 tests were performed, "negative" if the only result was negative, and "positive" if any of the 3 come back as positive (eg, patients with 1 negative HSV test result but 1 positive HSV test result are classified as positive).Positive results18 (5.7)4 (3.7)14 (6.7)Negative results211 (66.8)59 (54.6)152 (73.1)Not performed87 (27.5)45 (41.7)42 (20.2) MP workup†MP workup included culture, polymerase chain reaction of a lesion, polymerase chain reaction of the oropharynx/nasopharynx, and immunoglobulin G and immunoglobulin M serology: "not performed" only if none of the 4 tests were performed, "negative" if the only result was negative, and "positive" if any of the 4 come back as positive (eg, patients with 1 negative test result for MP and 1 positive test result for MP are classified as positive).Positive results159 (50.3)8 (7.4)151 (72.6)Negative results108 (34.2)64 (59.3)44 (21.2)Not performed49 (15.5)36 (33.3)13 (6.2)Treatment Antibiotics23256 (51.9)176 (84.6) Supportive‡Supportive care included wound care, barrier protection, nutrition, fluid and electrolyte replacement, and infection monitoring.21290 (83.3)123 (59.1) CS17773 (67.6)104 (50) IVIG11561 (56.5)54 (25.9) Antivirals8215 (13.9)67 (32.2) Immunosuppressive therapy§Immunosuppressive therapy included the conventional immunosuppressive therapies systemic cyclosporine (majority of cases) and methotrexate.3314 (12.9)12 (5.7) Anti-TNF88 (7.4)0CS, corticosteroids; DEN: drug-induced epidermal necrolysis; HSV, herpes simplex virus; IVIG, intravenous immunoglobulins; MP, Mycoplasma pneumoniae; RIME, reactive infectious mucocutaneous eruption; TNF, tumor necrosis factor.∗ HSV workup included serology, polymerase chain reaction, and culture: "not performed" only if none of the 3 tests were performed, "negative" if the only result was negative, and "positive" if any of the 3 come back as positive (eg, patients with 1 negative HSV test result but 1 positive HSV test result are classified as positive).† MP workup included culture, polymerase chain reaction of a lesion, polymerase chain reaction of the oropharynx/nasopharynx, and immunoglobulin G and immunoglobulin M serology: "not performed" only if none of the 4 tests were performed, "negative" if the only result was negative, and "positive" if any of the 4 come back as positive (eg, patients with 1 negative test result for MP and 1 positive test result for MP are classified as positive).‡ Supportive care included wound care, barrier protection, nutrition, fluid and electrolyte replacement, and infection monitoring.§ Immunosuppressive therapy included the conventional immunosuppressive therapies systemic cyclosporine (majority of cases) and methotrexate. Open table in a new tab CS, corticosteroids; DEN: drug-induced epidermal necrolysis; HSV, herpes simplex virus; IVIG, intravenous immunoglobulins; MP, Mycoplasma pneumoniae; RIME, reactive infectious mucocutaneous eruption; TNF, tumor necrosis factor. In RIME cases, Mycoplasma pneumoniae (MP) was isolated in 35% (51/146) by culture or polymerase chain reaction, and MP serology was positive in 83% (127/153). In DEN cases, anticonvulsants were the most common class of medications (44%, 47/108), and neurologic or psychiatric disorders were the most common underlying conditions. Trimethoprim/sulfamethoxazole was the single most common culprit drug (27%, 29/108), followed by lamotrigine (19%, 20/108). No deaths were reported with RIME (0/185), while the mortality rate with DEN was 4% (4/93). Treatment was reported for 97% (202/208) of RIME cases and 99% (107/108) of DEN cases. RIME cases most often received antibiotics (85%, 176/208), while DEN cases most often received supportive care (83%, 90/108). This dichotomy reflects the association of RIME with infection, leading to early initiation of antibiotics for presumed MP infection, and its relatively lesser severity compared to that of DEN, thus not requiring supportive care. A greater proportion of DEN cases compared to RIME cases received corticosteroids, intravenous immunoglobulins, and immunosuppressive therapies (primarily cyclosporine), again likely related to severity. Eight DEN cases and no RIME cases received anti–tumor necrosis factor therapy. The pediatric-specific definitions regrouped cases previously described with 10 different diagnoses into RIME and DEN to create 2 groups with more homogeneous causes, management, and outcomes. RIME and DEN are rare, necessitating a multicenter retrospective study with stringent inclusion criteria and central review to obtain a representative sample. The limitations include missing data, multiple persons involved in data entry, and possible misclassification of cases. Our study highlights the importance of standardized case definitions and data collection instruments to facilitate more complete prospective data collection. Analysis of treatment outcomes, recurrences, and complications are ongoing. Dr Lara-Corrales has received honoraria from Pierre Fabre, Amgen, Ipsen, Novartis, Pfizer, and Sanofi Genzyme and grants from AbbVie, Janssen, Clementia, Eli Lilly, Mayne Pharma, and Sanofi Genzyme. Dr Liy-Wong is advisor for Sanofi, Bayer, and Pfizer. Dr McKenzie is advisor for AbbVie, Amgen, Bausch, Bristol-Myers, Celgene, Galderma, Janssen, Leo Pharma, Lilly, Novartis, Pfizer, Sandoz, Sanofi, Sun Pharma, and UCB. Dr Rieder is advisor/consultant for, has received grants/honoraria from, and/or has served as a speaker for LEO Pharma, Pfizer, and Sanofi Genzyme. Drs Martinez-Cabriales, Coulombe, Aaron, Hussain, Linggonegoro, Barootes, Brandling-Bennett, Covelli, Kirkorian, Shah, Castelo-Soccio, Arkin, Heinze, Travis, Del Pozzo-Magana, Schoch, Monir, Glick, Uwakwe, Skillman, Hekman, Lethebe, and Ramien have no conflicts of interest to declare.

Introduction: Stress can impact mental and physical health, especially during adolescence and young adulthood, but the extent of its contribution to dental caries is poorly understood. The present study assessed the association between perceived stress, cortisol levels (in hair and saliva), and overall caries experience of adolescents and young adults aged 15-25 years. Methods: Hair and saliva samples were obtained from 93 participants free of periodontal disease. Cortisol in hair and saliva was determined using a competitive enzyme-linked immunosorbent assay. Participants completed a perceived stress questionnaire and underwent full-mouth oral examination by a calibrated examiner. Dental caries experience was based on the decayed, missing, and filled teeth (DMFT) index. Sociodemographic variables were also recorded. Results: There were significantly higher hair cortisol levels and perceived stress scale (PSS) scores in individuals with dental caries experience (DMFT >= 1) than in those without (DMFT = 0). However, there was no significant difference in salivary cortisol concentration. A binary logistic regression revealed that higher hair cortisol levels and greater scores on the perceived stress scale were associated with increased odds of having experienced dental caries. In contrast, no significant association was found between salivary cortisol concentration and dental caries. Using multivariable regression models, caries experience was found to be significantly associated with both hair cortisol levels and PSS scores. These associations remained statistically significant even after adjusting for sociodemographic variables. Conclusion: Hair cortisol levels and perceived stress have a significant association with dental caries experience, whereas salivary cortisol concentrations do not.

Individuals with high environmental sensitivity have nervous systems that are disproportionately receptive to both the protective and imperilling aspects of the environment, suggesting their mental health is strongly context-dependent. However, there have been few consolidated attempts to examine putative markers of sensitivity, across different levels of analysis, within a single cohort of individuals with high-priority mental health needs. Here, we examine psychological (self-report), physiological (hair hormones) and genetic (polygenic scores) markers of sensitivity in a large cohort of 1591 Syrian refugee children across two waves of data. Child-caregiver dyads were recruited from informal tented settlements in Lebanon, and completed a battery of psychological instruments at baseline and follow-up (12 months apart). Univariate and multivariate Bayesian linear mixed models were used to examine a) the interrelationships between markers of sensitivity and b) the ability of sensitivity markers to predict anxiety, depression, post-traumatic stress disorder, and externalising behaviour. Self-reported sensitivity (using the Highly Sensitive Child Scale) significantly predicted a higher burden of all forms of mental illness across both waves, however, there were no significant cross-lagged pathways. Physiological and genetic markers were not stably predictive of self-reported sensitivity, and failed to similarly predict mental health outcomes. The measurement of environmental sensitivity may have significant implications for identifying and treating mental illness, especially amongst vulnerable populations, but clinical utility is currently limited to self-report assessment.

Standardization and validation of in vitro drug metabolism is essential for pre-clinical drug development as well as for in vitro toxicity assays including the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA). Use of isolated liver microsomes (MIC) in in vitro testing has been utilized for a long time; however, the effect of species of origin and induction agents on the metabolic capacities of MIC is not adequately evaluated. In this study we investigated the impact of species of origin and induction agent on the capacity of MICs to bioactivate carbamazepine (CBZ) using cytotoxicity as a gross endpoint to measure the levels of cytotoxic metabolites generated by each type of MICs. Jurkat E6.1 cell line was used and MICs from human, rat, mouse, minipig and rabbit origin as well as rat MICs that is either non-induced or induced by phenobarbitone (PHB), dexamethasone (DEXA), 3-methylcholanthrene (3MC), clofibrate (CLOF) and isoniazid (INH) were investigated. MICs from minipig and rat MICs induced with 3MC exhibited the highest capacity to produce cytotoxic metabolites of CBZ. These findings will help optimize and standardize in vitro toxicity assays and provide guidance to pre-clinical investigation of drugs.

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For numerous issues of convenience and acceptability, hair hormone data have been increasingly incorporated in the field of war trauma and forced displacement, allowing retrospective examination of several biological metrics thought to covary with refugees’ mental health. As a relatively new research method, however, there remain several complexities and uncertainties surrounding the use of hair hormones, from initial hair sampling to final statistical analysis, many of which are underappreciated in the extant literature, and restrict the potential utility of hair hormones. To promote awareness, we provide a narrative overview of our experiences collecting and analyzing hair hormone data in a large cohort of Syrian refugee children (n = 1594), across two sampling waves spaced 12 months apart. We highlight both the challenges faced, and the promising results obtained thus far, and draw comparisons to other prominent studies in this field. Recommendations are provided to future researchers, with emphasis on longitudinal study designs, thorough collection and reporting of hair-related variables, and careful adherence to current laboratory guidelines and practices.